Development of a therapeutic anti-marinobufagenin antibody

National Institute On Aging

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Abstract

Although preeclampsia is a major cause of maternal and fetal mortality, its pathogenesis is not fully understood. Endogenous digitalis-like cardiotonic steroids (CTS) are implicated in the pathophysiology of preeclampsia, as illustrated by clinical observations that Digibind, a digoxin antibody which binds CTS, lowers blood pressure in patients with preeclampsia. Recently we reported that plasma levels of marinobufagenin (MBG), a bufadienolide vasoconstrictor CTS, are increased four-fold in patients with severe PE. In the present study, we compared levels of MBG in normal and preeclamptic placentae, and tested antibodies against MBG and ouabain for their interaction with the material purified from preeclamptic placentae via high-performance liquid chromatography (HPLC). Levels of MBG, but not that of endogenous ouabain, exhibited a four-fold elevation in preeclamptic placentae. The elution time of endogenous placental MBG-like immunoreactive material from reverse-phase HPLC column was identical to that of authentic MBG. Immunoassay based on Digibind did not detect cross-reactivity with HPLC containing ouabain-like immunoreactive material, but cross-reacted with HPLC fractions having retention time similar to that of MBG and other bufadienolides. In 2008 we also compared the in vivo efficacy of Digibind and monoclonal anti-MBG antibodies in two rat models of PE, in normal and diabetic pregnant rats rendered hypertensive by NaCl supplementation during days 14-20 of gestation. In both models, levels of MBG were substantially elevated, and anti-MBG antibody exceeded Digibind in its capacity to lower blood pressure and to reverse inhibition of Na/K-ATPase, a target enzyme for MBG. Our results demonstrate that both systemic and placental levels of MBG are significantly elevated in preeclampsia, and suggest that MBG is a potential target for immunoneutralization in patients with this syndrome.